A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

English version

Autoři: Edward Wolin ^aff001; Alain Mita ^aff001; Amit Mahipal ^aff002; Tim Meyer ^aff003; Johanna Bendell ^aff004; John Nemunaitis ^aff005; Pam N. Munster ^aff006; Luis Paz-Ares ^aff007; Ellen H. Filvaroff ^aff008; Shaoyi Li ^aff009; Kristen Hege ^aff008; Hans de Haan ^aff008; Monica Mita ^aff001
Působiště autorů: Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America ^aff001; Phase 1 Clinical Trials Program, Mayo Clinic, Rochester, MN, United States of America ^aff002; Experimental Cancer Medicine, University College Hospital, London, United Kingdom ^aff003; GI Oncology Research, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, United States of America ^aff004; Department of Oncology, Mary Crowley Cancer Research Center, Dallas, TX, United States of America ^aff005; Early Phase Clinical Research Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States of America ^aff006; Medical Oncology Department, Hospital Universitario 12 de Octubre, CNIO, Universidad Complutense and CiberOnc, Madrid, Spain ^aff007; Translational Medicine, Celgene Corporation, San Francisco, CA, United States of America ^aff008; Department of Statistics, Celgene Corporation, Summit, NJ, United States of America ^aff009
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0221994

Souhrn

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9–97.3%). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95% CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

Klíčová slova:

Biology and life sciences – Biochemistry – Research and analysis methods – Enzymology – Anatomy – Medicine and health sciences – Pathology and laboratory medicine – Physiology – Diagnostic medicine – Signs and symptoms – Pharmacology – Research design – Pharmacokinetics – Drug metabolism – Body fluids – Blood – Gastroenterology and hepatology – Oncology – Cancer treatment – Clinical research design – Adverse events – Biomarkers – Toxicology – Toxicity – Diarrhea – Enzyme inhibitors – Kinase inhibitors

Zdroje

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A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

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